Atherosclerosis and its clinical consequences, coronary heart disease (CHD), stroke and peripheral vascular disease, represent an enormous burden on the health care systems of the industrialized world. In the United States alone, greater than one half million deaths are attributed to CHD each year. This toll is expected to grow as the average age of the population increases and as an epidemic in obesity and diabetes continues to grow.
Inhibition of CETP is a promising but unproven approach to reducing the incidence of atherosclerosis. Statins have reduced the incidence of CHD by reducing LDL-cholesterol (the “bad cholesterol”), but are relatively ineffective at raising HDL-cholesterol (“the good cholesterol”). CETP inhibitors raise HDL-cholesterol, and may provide a potent new tool for reducing CHD and atherosclerosis in the general population. Torcetrapib was the first CETP inhibitor to be tested in human patients. The pivotal clinical trial of torcetrapib, an outcomes study, was terminated early because of higher mortality in the test group of patients who were taking the drug concomitantly with a statin compared with a group of patients who were taking a placebo and a statin. Subsequent research has suggested that the higher mortality in the test group was caused by off-target activity and was not related to CETP inhibition. Two newer drugs, anacetrapib and dalcetrapib, have also been in Phase III outcomes trials. The dalcetrapib trial was terminated early because an interim review found that there was no clinical benefit to the patients who were taking dalcetrapib, but that there were also no safety issues with the drug. Anacetrapib is currently being studied in an outcomes trial which will not be completed until about 2017. Data from an earlier non-outcomes trial of anacetrapib indicated that anacetrapib is unlikely to have the same kinds of safety issues that were observed with torcetrapib.
A process for making anacetrapib was previously disclosed in a published patent application (WO 2007/005572).